Chapter 6- Part II

• Bone Development• Bone growth and hormonal regulation

of bone growth• Bone remodeling

– Regulation of blood Ca2+

• Bone Repair• Osteomalacia, Rickets, Osteoporosis

– Causes and Treatments

Can you identify all of these parts of a bone?

What is the definition of

• Ossification

• Calcification

Formation of the Bony Skeleton• Begins at week 8 of embryonic development

• Ossification– Intramembranous ossification – bone develops from

a fibrous membrane– Endochondral ossification – bone forms by replacing

hyaline cartilage

Endochondral and Intramembranous ossification

• Both processes are more similar than they are different– Same cells participate and do similar things

• At biochemical and cellular level, many of the same events occur

• Differences:– Site of activity– Organization of activity– Numbers of centers of ossification– What is replaced

Intramembranous ossification

– Also called dermal ossification

– Occurs in fibrous membrane of mesenchyme

– Flat bones of the skull, mandible, and clavicle

You lucky ducks don’t have to know the steps of this process!

The Birth of Bone

• When new bone is born, either during development or regeneration, it often starts out as spongy bone (even if it will later be remodeled into compact bone)

Endochondral OssificationNote: you DO have to know this one

• Begins in the second month of development• Uses hyaline cartilage “bones” as models for bone

construction then ossifies cartilage into bone • Common, as most bones originate as hyaline

cartilage• This is like a “trick” the body uses to allow long

bones to grow in length when bones can only grow by appositional growth

Bone formation in a chick embryo

• Stained to represent hardened bone (red) and cartilage (blue)

• : This image is the cover illustration from The Atlas of Chick Development by Ruth Bellairs and Mark Osmond, published by Academic Press (New York) in 1998

Bone formation in a human embryo

Endochondral Ossification• Bone replaces a cartilaginous model (hyaline)• Occurs in most bones 1. Cells of the perichondrium differentiate to osteoblasts and form a bone collar

around the outside (a periosteum)2. Chondrocytes at center of model grow large, cause calcification to happen all

around themselves, and then they die, leaving behind big spaces (fancy term= cavitation)

3. Spaces invaded by periosteal bud, (blood vessels, nerve, lymphatic vessel, osteoclasts, osteoblasts)

• Osteoclasts and -blasts arrive. Set up primary ossification center, and bone growth occurs (as spongy bone, trabeculae) spreads along shaft of bone, toward ends.

4. Primary ossification center grows, and a medullary cavity is carved out. Cartilage continues to grow at the epiphyseal side of the shaft.

5. At or after birth, the centers of each epiphysis also begin to be replaced by bone, each end is a secondary ossification center

• At the epiphyseal plate (growth plate), as long as cartilage growth outpaces replacement by bone, bone length continues.

Formation ofbone collararound hyalinecartilage model.

Hyalinecartilage

Primaryossificationcenter

Bone collar

1

Cavitation ofthe hyaline carti-lage within thecartilage model.

Deterioratingcartilagematrix

2 Invasion ofinternal cavitiesby the periostealbud and spongybone formation.

3

Formation of themedullary cavity asossification continues;appearance of sec-ondary ossificationcenters in the epiphy-ses in preparationfor stage 5.

Epiphysealblood vessel

Secondaryossificatoncenter

Medullarycavity

4

Ossification of theepiphyses; whencompleted, hyalinecartilage remains onlyin the epiphyseal platesand articular cartilages.

Epiphysealplatecartilage

Articularcartilage

Spongybone

5

Stages of Endochondral Ossification

Endochondral Ossification

…and the race is on

When secondary ossification is complete, where would you find

hyaline cartilage?

Endochondral Ossification: Step 5 (Elongation)

• Epiphyses fill with spongy bone but cartilage remains at two sites:– ends of bones within the

joint cavity = articular cartilage

– cartilage at the metaphysis = epiphyseal cartilage (plate)

Figure 6–9 (Step 6)

What occurs at the epiphyseal plate, or growth plate?

…and the race is on

Postnatal Bone Growth

• Growth in length of long bones– Cartilage on the side of the epiphyseal plate

closest to the epiphysis is relatively inactive– Cartilage abutting the shaft of the bone

organizes into a pattern that allows fast, efficient growth

– Cells of the epiphyseal plate proximal to the resting cartilage form three functionally different zones: growth, transformation, and osteogenic

Functional Zones in Long Bone Growth

• Growth zone – cartilage cells undergo mitosis, pushing the epiphysis away from the diaphysis

• Transformation zone – older cells enlarge, the matrix becomes calcified, cartilage cells die, and the matrix begins to deteriorate

• Osteogenic zone – new bone formation occurs

Growth in Length of Long Bone

Figure 6.9

Growth Plate

Epiphyseal cartilages undergo ossification and become epiphyseal lines

More on Postnatal bone growth

• Remember that bone growth can only occur from the outside (appositional growth). So this type of endochondral growth is a way for bones to grow from the inside and lengthen because it is the cartilage that is growing, not the bone

Key Concept

• As epiphyseal cartilage grows through the division of chondrocytes it pushes the ends of the bone outward in length.

• At the “inner” (shaft) side of the epiphyseal plate, recently born cartilage gets turned into bone, but as long as the cartilage divides and extends as fast or faster than it gets turned into bone, the bone will grow longer

Long Bone Growth and Remodeling

• Growth in length – cartilage continually grows and is replaced by bone as shown

• Remodeling – bone is resorbed and added by appositional growth as shown – compact bone thickens and strengthens long

bones with layers of circumferential lamellae

Long Bone Growth and Remodeling

Figure 6.10

Appositional Growth

Epiphyseal Lines

• When long bone stops growing, between the ages of 18 – 25:– epiphyseal cartilage disappears – epiphyseal plate closes– visible on X-rays as an epiphyseal line

• At this point, bone has replaced all the cartilage and the bone can no longer grow in length

Bone growth during youth

• What is the most important hormone for bone growth during infancy and childhood?

• Where in the body does this hormone have its most critical effects?

• Thyroid hormone, and sex hormones also play a role in bone growth

• Primary cause of gigantism? Dwarfism?

What do we need to grow healthy bones?

Rickets

In the adult, bone remodeling occurs constantly and also when we break a bone

• What does bone remodeling involve?

• Bone remodeling is a continual, life-long process– 5% of our bone mass is recycled/week– Spongy bone is replaced every 3-4 years– “Old, not-remodeled” bone becomes brittle– If removal is faster than deposition, bones get weaker!

Bone deposition & bone resorption

• Osteoblasts build bone

– Lay down osteoid

– Osteoid calcifies when calcium and phosphate reach specific concentrations and in the presence of alkaline phosphatase

• Osteoclasts dissolve bone

– Release lysosomal enzymes and hydrocholric acid

– Phagocytose demineralized matrix, dead osteocytes

What regulates and controls bone remodeling?

#1 BLOOD CALCIUM LEVELS!

• First, where/how does the body GET “new”calcium?– From birth to age 10, children need 400-800 mg/day – From ages 11-24 need 1200-1500 mg/day

• Second, why is it so critical that blood calcium levels are maintained? Or, what physiological processes are affected by changes in calcium?

• What hormones have the most important role in calcium regulation?

• Parathyroid Hormone (PTH) is released in response to LOW blood Ca2+ levels

•What does PTH do once released? What cells of the body have PTH receptors?

•Is this a negative or positive feedback loop?

Osteoclastsdegrade bonematrix and release Ca2+

into blood.

Parathyroidglands

Thyroidgland

Parathyroidglands releaseparathyroidhormone (PTH).

StimulusFalling bloodCa2+ levels

PTH

Calcium homeostasis of blood: 9–11 mg/100 ml

PTH increases blood calcium levels

via VitD

• Stimulates osteoclasts• Decreases Ca2+

excretion at kidneys• Stimulates calcium

absorption at gut, via calcitriol (Vit D)

Calcitonin and Ca2+ regulation

• Calcitonin is a hormone released by cells (parafollicular cells) of the thyroid

• At physiological levels, calcitonin does not have an important role in calcium regulation.

• Mixed results for calcitonin in treatment of osteoporosis or hypercalcemia

CT

osteoclast

may

Bone remodeling

• #2- is also controlled by mechanical stress• What causes stress on bones?• Wolff’s law holds that a bone grows or remodels

in response to the demands placed on it– Examples of Wolff’s law in action? Inaction?

Cross-sectionaldimension of the humerus

Addedbone matrixcounteractsadded stressServing arm Nonserving arm

Bone remodeling is controlled by mechanical stress

• How does Wolff’s law work?• Deforming a bone (mechanical stress) produces a small

electrical current– Osteocytes and/or collagen molecules act as

‘biosensors’– In a frequently loaded or ‘pulled’ region of a bone,

growth is stimulated– Can magnets or applied voltage increase bone

growth/healing?

Bone Fractures

• Nondisplaced or displaced fracture• Incomplete or complete fracture• Linear or transverse fracture• Closed (simple) or open (compound) fracture

• How is a fracture treated?

Bone Repair• When bones are fractured, blood vessels are broken1. A large blood clot (hematoma) forms around the injured area2. Capillaries grow into hematoma and dead cells, pathogens and

debris are cleaned up by immune cells. • Fibroblasts, osteoblasts, -clasts migrate to area, start to rebuild.

Some fibroblasts differentitate into chondrocytes. Fibrocartilage (soft) callus formed.

3. Over time, the cartilage is replaced by bone.Bone callus- exists from 3-4 weeks after injury to 2-3 months later

4. Remodeling of the affected area may continue for months to years.

How do fractures repair?

Hematoma Externalcallus

Bonycallus ofspongybone

Healedfracture

Newbloodvessels

Spongybonetrabecula

Internalcallus(fibroustissue andcartilage)

1 A hematoma forms. 2 Fibrocartilaginouscallus forms.

3 Bony callus forms. 4 Boneremodelingoccurs.

The first x-ray was taken right after a fracture. The second was 2 months later, showing some callus. Notice that the leg is now in a cast, so the entire bone looks a little more dense and fuzzy. The last x-ray was 4 months after the fracture, showing a good callus. The bone now can bear weight, but it will take many months to remodel the area and complete the repair. http://depts.washington.edu/bonebio/ASBMRed/growth.html

Clinical advances in bone repair• Electrical stimulation of fracture site.

– results in increased rapidity and completeness of bone healing– electrical field may prevent  parathyroid hormone from activating

osteoclasts at the  fracture site thereby increasing formation of bone and minimizing breakdown of bone,

• Ultrasound.  – Daily treatment results in decreased healing time of  fracture by about

25% to 35% in broken arms and shinbones. Stimulates cartilage cells to make bony callus.

• Free vascular fibular graft technique. – Uses pieces of fibula to replace bone or splint two broken ends of a

bone.  Fibula is a non-essential bone, meaning it does not play a role in bearing weight; however, it does help stabilize the ankle.

• Bone substitutes.– synthetic material or crushed bones from cadavers serve as bone fillers

(Can also use sea coral).  

Imbalances that affect bone

• Osteomalacia

• Rickets

• Paget’s disease

• Osteoporosis

Notice what happens in osteoporosis

•This graph shows values for bone mineral density at the hip in Caucasian men and women and African-American men and women. •With aging, bone density decreases in all groups. This inevitable bone loss is frequently the cause of osteoporosis. Data are from a study by Looker, Osteoporosis International 1998

Bone density changes with age

Osteoporosis

• What is it?

• What does it look like?

• What bones and parts of bones are most strongly affected?

• Who is most likely affected?

• What are the treatments?

Osteoporosis• In osteoporosis bone resorption outpaces bone deposit

– Which cells are more active, osteoblasts or osteoclasts?

• Osteoporosis- reduction in bone compromises normal function

• In the U.S., 10 million individuals are estimated to already have the disease and almost 34 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis.

• Over age 45, occurs in ~30% of women, ~18% men• Risk factors?• Osteoporotic fractures cost $18 billion per year in 2002

dollars • Are all bones and parts of bones affected equally?

Osteoporosis

• Epiphyses, vertebrae, and the jaw lose more mass than other sites

• How does this explain loss of height? Loss of teeth, and fragile limbs?

Osteoporosis

Osteoporosis

• Animation of bone remodelinghttp://courses.washington.edu/bonephys/opmovies.html

• http://courses.washington.edu/bonephys/opmovies.html

• Treatments? Risks?– Calcium, Vit D, moderate exercise– Estrogens at menopause (HRT)?– Alendronate (Bisphosphonates)– SERMs- Selective Estrogen Receptor Modulators– Statins